By Billy Candra 
LA JOLLA, CA – A groundbreaking study from the Salk Institute has unveiled a critical role for estrogen-related receptors (ERRs) in the intricate mechanisms governing energy metabolism and muscle function. Published in the prestigious journal Proceedings of the National Academy of Sciences on May 12, 2025, these findings suggest that targeting these receptors could unlock novel therapeutic pathways for a range of debilitating conditions characterized by metabolic dysfunction and profound muscle weakness. The research pinpoints ERRs as potentially indispensable drivers of mitochondrial growth and activity within muscle cells, offering a promising avenue for pharmacological intervention where current treatments are often limited.
The Mitochondrial Imperative: Fueling Life and Fighting Dysfunction
At the very core of cellular life, mitochondria—often referred to as the "powerhouses" of the cell—are tirelessly engaged in converting the food we consume into adenosine triphosphate (ATP), the usable energy currency that powers virtually all biological processes. This cellular-level metabolism is particularly vital in muscle cells, which demand substantial energy reserves to facilitate movement, maintain posture, and perform various physical tasks. The efficiency and health of these tiny organelles are paramount for overall well-being.
However, mitochondrial function is not always optimal. An estimated 1 in 5,000 individuals is born with genetic mitochondrial disorders, a diverse group of conditions that can affect nearly any organ system and lead to a wide spectrum of symptoms, from muscle weakness and fatigue to neurological problems and organ failure. Beyond these congenital conditions, millions more worldwide develop metabolic dysfunction later in life. This acquired form of mitochondrial impairment is increasingly recognized as a significant contributor to, or consequence of, common age-related diseases and chronic illnesses. Conditions such as cancer, multiple sclerosis (MS), heart disease, Alzheimer’s disease and other forms of dementia, and even the general frailty associated with aging, frequently exhibit underlying metabolic dysregulation linked to mitochondrial compromise. The widespread impact of these disorders underscores the urgent need for effective therapeutic strategies.
A Legacy of Discovery: The Salk Institute’s Pioneering Work
The current breakthrough stands on the shoulders of decades of pioneering research conducted at the Salk Institute, a world-renowned independent research organization dedicated to fundamental discoveries in biology. A central figure in this legacy is Ronald Evans, a professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk, and the senior author of the new study.
Evans’ laboratory has a distinguished history of unraveling the complexities of nuclear hormone receptors, a super-family of proteins that play pivotal roles in regulating gene expression in response to hormones and other signaling molecules. It was in the 1980s that Evans led the landmark discovery of this entire family of proteins, establishing a new paradigm in understanding how hormones control physiological processes. These hormone-activated receptors function as molecular switches: they attach to specific sequences within our DNA and, in doing so, dictate which genes are turned "on" or "off," thereby controlling a vast array of biological functions from development to metabolism.
Among the many branches of this intricate family of receptors are the estrogen-related receptors (ERRs). Evans’ lab first discovered ERRs in 1988, recognizing their unique characteristics and early indications of their involvement in energy metabolism. Unlike classic estrogen receptors, which are activated by the hormone estrogen, ERRs are constitutively active or activated by specific metabolic signals, operating independently of estrogen yet sharing structural similarities. Their prevalence in metabolically demanding organs such as the heart, brain, and skeletal muscle has long intrigued researchers, suggesting a specialized role in energy homeostasis. This led Evans’ team to delve deeper into their potential function in regulating metabolism within skeletal muscle, an organ with immense energy requirements.
Unlocking Muscle Energy: The Role of Estrogen-Related Receptors
Skeletal muscles are highly dynamic tissues, with their energy demands fluctuating dramatically. During periods of rest, they maintain a baseline metabolic rate, but during exercise, their need for ATP skyrockets. This increased energy demand triggers a remarkable adaptive process known as mitochondrial biogenesis, wherein muscle cells increase both the number and energetic capacity of their mitochondria to meet the heightened fuel requirements. This natural response to physical activity is a cornerstone of fitness and endurance.
However, for individuals suffering from muscular and metabolic disorders, the very act of exercise—which is so crucial for stimulating mitochondrial growth—can be challenging, painful, or even impossible. This clinical reality has driven scientists to seek alternative, pharmacological methods to stimulate mitochondrial biogenesis, essentially seeking to mimic the beneficial effects of exercise.
"Mitochondria are our cells’ energy factories, so the more we exercise, the more mitochondria our muscles need," explains Weiwei Fan, a staff scientist in Evans’ lab and the first author of the study. "This got us thinking – if we could understand how exercise induces mitochondrial biogenesis, we might be able to target those same mechanisms pharmacologically to trigger this process in people who are too weak to exercise."
To systematically investigate the role of ERRs in muscle cell metabolism, Fan and his colleagues employed genetically modified mouse models. They selectively deleted three different forms of estrogen-related receptors—alpha (ERRα), beta (ERRβ), and gamma (ERRγ)—specifically within the muscle tissues of these mice. The researchers then meticulously examined the resulting physiological and molecular effects on muscle function and mitochondrial health.
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Decoding ERRα’s Indispensable Role in Exercise Adaptation:
The initial observations revealed that ERRα was the most abundant type of estrogen-related receptor present in muscle tissue. Surprisingly, the isolated loss of ERRα alone had only mild impacts on muscle tissue under normal, resting conditions. This muted effect was attributed to the compensatory activity of ERRγ. Although ERRγ constitutes a mere 4% of the total estrogen-related receptors in muscle, it demonstrated a remarkable ability to compensate for the absence of ERRα, maintaining mitochondrial function at baseline. However, the deletion of both ERRα and ERRγ led to severe impairments in muscle mitochondrial activity, significantly altering their shape and size, and highlighting the critical, synergistic role of these two receptor types.The question then arose: why the apparent redundancy, particularly the high abundance of ERRα, if ERRγ could compensate under normal circumstances? The Salk team hypothesized that ERRα’s true indispensable function would become apparent under conditions of metabolic stress, specifically during exercise, when muscles need to adapt and grow. To test this, the researchers subjected their mice to controlled exercise regimens using mechanical wheels. This exercise robustly triggered mitochondrial biogenesis in control mice, providing an ideal experimental setup to assess ERRα’s involvement. The results were striking: the loss of ERRα alone was sufficient to completely block exercise-induced mitochondrial biogenesis. This pivotal finding established ERRα as an essential mediator of muscle adaptation to physical activity, acting as a crucial "on" switch for mitochondrial proliferation in response to increased energy demand.
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The PGC1α-ERRα Partnership: A Druggable Advantage:
Previous research had identified another key protein, PGC1α (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha), as a master regulator of mitochondria throughout the body. PGC1α is known to orchestrate mitochondrial biogenesis and function in various tissues. However, PGC1α itself cannot directly bind to DNA to activate genes. Instead, it acts as a coactivator, relying on partner proteins—transcription factors—to physically interact with the genome and execute its regulatory functions. This indirect mode of action makes PGC1α a more challenging target for therapeutic drug development, as drugs would need to modulate its interactions with multiple, diverse partners.The Salk team’s investigation into muscle cells post-exercise revealed a critical interaction: PGC1α was found to partner directly with ERRα to drive mitochondrial biogenesis. Crucially, unlike PGC1α, ERRα possesses the ability to bind directly to the DNA sequences of mitochondrial energetic genes and activate their expression. This direct DNA-binding capability positions ERRα as a highly attractive and more "druggable" target for pharmacological intervention. By developing compounds that activate ERRα, scientists could potentially directly upregulate mitochondrial gene expression, thereby enhancing mitochondrial performance and energy production in muscles.
A New Therapeutic Horizon for Metabolic Disorders
The implications of these findings are profound, particularly for individuals afflicted with metabolic disorders and muscle-wasting conditions. Muscular dystrophy, for example, is a group of genetic diseases characterized by progressive weakness and degeneration of skeletal muscles. Patients with muscular dystrophy often experience severe muscle fatigue and a diminished capacity for physical activity, leading to a vicious cycle where lack of exercise further exacerbates muscle weakness and metabolic decline. Current treatments primarily focus on symptom management, with no definitive cure.
"Our findings, published in Proceedings of the National Academy of Sciences on May 12, 2025, indicate that developing a drug to boost estrogen-related receptors could be a powerful way to restore energy supplies in people with metabolic disorders, such as muscular dystrophy," the authors stated. Such a drug could potentially stimulate mitochondrial biogenesis and improve muscle function, offering a much-needed therapeutic breakthrough.
The advantage of targeting ERRs lies in their direct role in gene regulation. "Estrogen-related receptors look a lot like classic estrogen receptors, but their function has been much less understood," says Ronald Evans. "Our lab discovered estrogen-related receptors in 1988 and was one of the first to recognize their role in energy metabolism. Now we’ve learned that estrogen-related receptors are indispensable drivers of mitochondrial growth and activity in our muscles. This makes them a really promising target to treat muscle weakness and fatigue in many different diseases that involve metabolic dysfunction." This clarity in mechanism provides a more direct and potentially effective approach to drug design compared to targeting a coactivator like PGC1α.
Beyond Muscle: Systemic Health Benefits
The potential benefits of activating estrogen-related receptors extend far beyond just muscle tissue. Given the widespread importance of mitochondrial function across all organ systems, improving energy metabolism in one area could trigger beneficial cascades throughout the body.
"Our findings suggest that activating estrogen-related receptors could not only help fuel people’s muscles, but it could also have other beneficial effects across the whole body," says Weiwei Fan. "Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart."
The brain, being the most metabolically active organ in the body, is particularly vulnerable to mitochondrial dysfunction, which is implicated in neurodegenerative diseases like Alzheimer’s and Parkinson’s. Similarly, the heart, a continuously working muscle, relies heavily on efficient mitochondrial function; compromised energy production is a hallmark of various cardiac pathologies, including heart failure. By enhancing mitochondrial health systemically, ERR-targeting therapies could offer a broad spectrum of protective and restorative effects, potentially improving quality of life for millions suffering from diverse age-related and chronic diseases.
The Road Ahead: Future Research and Collaboration
Understanding how estrogen-related receptors function in muscle cells creates new opportunities to treat all parts of the body affected by mitochondrial dysfunction. The Salk team’s next steps involve further exploring the nuanced functions and regulatory mechanisms of both alpha- and gamma-type receptors. This deeper understanding may uncover additional therapeutic targets or refine strategies for activating these crucial metabolic regulators.
The collaborative nature of this research is evident in the extensive list of contributing authors: Hui Wang, Lillian Crossley, Mingxiao He, Hunter Robbins, Chandra Koopari, Yang Dai, Morgan Truitt, Ruth Yu, Annette Atkins, and Michael Downes of Salk; Tae Gyu Oh of Salk and the University of Oklahoma; and Christopher Liddle of the University of Sydney, Australia. The work received substantial support from a consortium of prestigious funding bodies, including the National Institutes of Health (P01HL147835, DK057978, DK120515, 1R21OD030076, CCSG P30CA23100, CCSG P30 CA014195, CCSG P30 CA014195, P30 AG068635), the Department of the Navy (N00014-16-1-3159), the Larry L. Hillblom Foundation, Inc. (2021-D-001-NET), the Wu Tsai Human Performance Alliance, the Henry L. Guenther Foundation, and the Waitt Foundation.
These collective efforts underscore the scientific community’s commitment to translating fundamental biological discoveries into tangible health benefits. The Salk Institute’s latest findings on estrogen-related receptors mark a significant stride forward in the quest to combat metabolic dysfunction and its devastating consequences, offering a beacon of hope for future therapeutic interventions.
